This is a study in clinical psychopharmacology. The therapeutic effect of lithium (Li ion) in manic-depressive illness raises important unsolved questions, such as: In what ways do manic-depressives differ from normal subjects? What is the mechanism of action of Li ion? Why do some patients fail to respond to Li ion concentrations that would be effective in others? In studies leading to this proposal, we have developed a microanalytical technique for Li ion several orders of magnitude more sensitive than existing methods. We have used this technique to assess contributions of four major flux pathways to Li ion influx and efflux across membranes of erythrocytes as a model cell system. We now propose to do comparative studies of patients initially characterized as acute manics, their relatives, and normal control subjects. The project emphasizes the use of the Research Diagnostic Criteria with application of the Schedule for Affective Diseases and Schizophrenia to reduce heterogeneity in the patient group, and the use of our microanalytical technique to measure Li ion fluxes at realistic concentrations and times. Our goals are: 1. To perfect a method for routine clinical monitoring of plasma and erythrocyte Li ion concentrations of patients, using only a finger prick blood sample. 2. To examine whether pharmacokinetic differences among patients in Li ion concentrations contribute to differences in response or have implications for dose schedules. 3. As our major goal, to compare subjects' erythrocytes in the following measurements: contributions of the four flux pathways to Li ion fluxes; choline fluxes; ion concentrations; metabolic state; ATP-ase activity; and blood count parameters. Nitrogenous cations will be used to amplify inter-subject differences exhibited by Li ion itself. 4. To devise rapid tests for predicting response to Li ion, optimal dose, and dose schedule for patients not yet on Li ion therapy.